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Targeting Senescence for Biomarkers and Therapeutics

针对衰老的生物标志物和治疗方法

基本信息

批准号：
10197119
负责人：
Anil Bhushan
金额：
$ 53.78万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197119
关键词：
Address Apoptosis Autoimmune Diseases Automobile Driving BCL2 gene Basement membrane Beta Cell Biological Markers Blood specimen Cell Aging Cells Cellular Metabolic Process Cellular Stress Response Cellular biology Characteristics Chemotaxis Development Diabetes Mellitus Disease Disease Progression Disease model Environment Etiology Extracellular Matrix Ferritin Functional disorder Human Human Activities Hyperglycemia Immune Immune response Immunologic Surveillance Inbred NOD Mice Insulin-Dependent Diabetes Mellitus Invaded Laboratories Measures Mediating Mediator of activation protein Morphology Mus Natural History Organ Organ Donor Pathogenesis Pathway interactions Peripheral Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Property Proteins Reporting Role Sampling Serum Structure Structure of beta Cell of islet Testing Therapeutic Tissues Translating Tumor-infiltrating immune cells Work biomarker discovery cell type clinically relevant design drug efficacy experimental study in vivo islet migration mimetics monocyte mouse model novel novel therapeutic intervention paracrine preservation prevent repository senescence small molecule tool virtual

项目摘要

Type 1 Diabetes is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. While there has been significant progress in understanding immune-mediated beta cell destruction, the role of beta cell dysfunction in the underlying etiology of T1D is less clear. We have discovered that pancreatic beta cells acquire a proinflammatory secretome reminiscent of SASP during T1D in mice and human. SASP beta cells can remodel the islet environment in a paracrine manner by promoting bystander senescence and immune surveillance. We have developed drugs that selectively eliminated SASP beta cells without altering the abundance of the major immune cell types involved in the disease. Significantly, elimination of SASP beta cells halted progression of beta cell destruction and was sufficient to prevent diabetes. In this proposal, we focus on human beta cells and characterize the non-cell autonomous effects of SASP on islet microenvironment and develop drugs that can selectively target human SASP beta cells. We utilize the secretory properties of SASP beta cells to identify biomarkers that can report on the efficacy of drug treatment and progression of the disease.

1型糖尿病是一种器官特异性自身免疫性疾病，其特征是由于胰岛β细胞进行性丧失而导致的高血糖。虽然在理解免疫介导的β细胞破坏方面已经取得了重大进展，但β细胞功能障碍在T1D潜在病因中的作用尚不清楚。我们已经发现，在小鼠和人类的T1D期间，胰腺β细胞获得了一个类似于SASP的前炎性分泌体。SASPβ细胞可以通过促进旁观者衰老和免疫监视，以旁分泌的方式重塑胰岛环境。我们已经开发出选择性地消除SASPβ细胞的药物，而不会改变与这种疾病有关的主要免疫细胞类型的丰度。值得注意的是，SASPβ细胞的消除阻止了β细胞破坏的进展，并足以预防糖尿病。在这项建议中，我们将重点放在人的β细胞上，并表征SASP对胰岛微环境的非细胞自主效应，并开发能够选择性靶向人SASPβ细胞的药物。我们利用SASPβ细胞的分泌特性来识别可以报告药物治疗效果和疾病进展的生物标记物。